Hu Yinghong, Lee Young-Tae, Kaech Susan M, Garvy Beth, Cauley Linda S
Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032;
Georgia State University, Atlanta, GA 30302;
J Immunol. 2015 Mar 1;194(5):2407-14. doi: 10.4049/jimmunol.1402369. Epub 2015 Jan 30.
Tissue-resident memory CD8 T cells are a unique subset of virus-specific CTLs that bolster local immune responses after becoming lodged in previously infected tissues. These cells provide enhanced protection by intercepting returning pathogens before a new infection gets established. In contrast, central memory CD8 T cells circulate in the bloodstream and proliferate in secondary lymphoid organs before replenishing effector and memory CD8 T cell populations in remote parts of the body. Both populations of virus-specific memory CD8 T cells participate in immunity to influenza virus infection; however, the signaling pathways that instruct developing memory CD8 T cells to distribute to specific tissues are poorly defined. We show that TGF-β promotes the development of pulmonary tissue-resident memory T cells via a signaling pathway that does not require the downstream signaling intermediate Sma- and Mad-related protein (Smad)4. In contrast, circulating memory CD8 T cells have no requirement for TGF-β but show signs of arrested development in the absence of Smad4, including aberrant CD103 expression. These signaling pathways alter the distribution of virus-specific CTLs in the lungs but do not prevent robust cytokine responses. Our data show that Smad4 is required for normal differentiation of multiple subsets of virus-specific CD8 T cells. In normal circumstances, Smad4 may be activated via a pathway that bypasses the TGF-β receptor. Improved understanding of these signaling pathways could be used to augment vaccine-induced immunity.
组织驻留记忆性CD8 T细胞是病毒特异性CTL的一个独特亚群，它们在驻留在先前感染的组织中后可增强局部免疫反应。这些细胞通过在新感染建立之前拦截返回的病原体来提供增强的保护。相比之下，中枢记忆性CD8 T细胞在血液中循环，并在次级淋巴器官中增殖，然后在身体远端补充效应性和记忆性CD8 T细胞群体。这两种病毒特异性记忆性CD8 T细胞群体都参与对流感病毒感染的免疫；然而，指导发育中的记忆性CD8 T细胞分布到特定组织的信号通路尚不清楚。我们发现，转化生长因子-β（TGF-β）通过一条不需要下游信号中间体小母羊相关蛋白（Smad）4的信号通路促进肺组织驻留记忆性T细胞的发育。相比之下，循环记忆性CD8 T细胞不需要TGF-β，但在没有Smad4的情况下显示出发育停滞的迹象，包括异常的CD103表达。这些信号通路改变了肺中病毒特异性CTL的分布，但并不妨碍强大的细胞因子反应。我们的数据表明，Smad4是病毒特异性CD8 T细胞多个亚群正常分化所必需的。在正常情况下，Smad4可能通过一条绕过TGF-β受体的途径被激活。对这些信号通路的更好理解可用于增强疫苗诱导的免疫力。
